In this analysis, levels of TGF-β1 did not predict development of incident rOA, OST, or JSN in the hip or knee. The small increase in progressive knee rOA risk with higher TGF-β1 was not statistically significant, despite a large proportion of the sample having these outcomes. There was no association between TGF-β1 levels and progression of rOA in additional joint sites (across both knees and both hips). The small, non-significant alterations in risk identified in the current study, despite a large overall sample
size and fairly large proportion with most of the outcomes of interest, demonstrate that serum TGF-β1 is not likely to be a robust biomarker of rOA. This is in agreement with our findings in a cross-sectional study looking at prevalence and severity of radiographic OA, in which no significant associations were seen with levels of serum TGF-β1(8
Despite our prior findings of greater OST burden in African Americans (20
) and the trend toward higher TGF-β1 with more severe OST grades (8
), we did not see any interactions by race in the current analysis, and stratified analysis did not reveal significant differences. We had limited power to detect interactions and differences by race due to a small number of outcomes by race in stratified analyses. There was a suggestion of reduction in risk of both incident and progressive OST at the knee with higher baseline serum TGF-β1 levels among African Americans. However, the differences were not statistically significant, and there were small numbers for some of the outcomes following stratification, so these findings must be considered very cautiously. One could speculate that there may be higher levels of synovial TGF-β1 acting locally leading to these findings, but we did not have synovial fluid levels to evaluate this.
Prior studies of TGF-β1 in OA have failed to show consistent results. Otterness and colleagues assessed a panel of biomarkers in a case control study with 12 month follow up and biomarker measurement at multiple time points. In agreement with our cross-sectional study of the current cohort (8
), they found that levels of TGF-β1 did not discriminate between individuals with OA (by ACR criteria) and controls (7
). They did identify a borderline association between baselineTGF-β1 levels and change in clinical status (as determined by change in symptoms and patient/physician assessments) at 12 months, primarily
because of an association between patient global assessment and baseline TGF-β1 (10
). Another group, using radiographic data in addition to clinical criteria, showed a small, negative correlation (r =−0.19, p value 0.01) between baseline TGF-β1 level and K-L grade at the knee, but in contrast to the Otterness study, no associations were seen with clinical outcomes at baseline or 18 month follow-up (9
). These studies, in combination with the negative results of the current study, suggest that serum TGF-β1 is unlikely to be a useful biomarker for future study in OA.
Limitations to this analysis include the lack of symptoms data, and the small number of hips demonstrating progression, especially for those progressing beyond K-L grade 2 and with progressive JSN. We had only a single measurement of TGF-β1 at baseline rather than repeated measures at multiple timepoints. We had radiographic data only for the hips and knees, and therefore cannot account for OA at other joint sites. As in most large epidemiologic studies (26
), the hip radiographs in this study are non-weightbearing, and there remains controversy in the literature regarding the benefits of weightbearing versus non-weightbearing standardized hip radiographs (27
). Also, and primarily for logistic reasons, because of the size and complexity of the parent study, it was not possible to control for diurnal variation, exercise levels, postural changes, or dietary intake that may alter serum TGF-β1 levels (29
). A study of diurnal variation in OA biomarkers by Kong and colleagues demonstrated a correlation between TGF-β1 levels and summed K-L grade for both knees, but only at the end of the day (r2
=0.35, p=0.006), with no correlation between K-L grade and morning TGF-β1 levels, before or after food intake or activity (30
). The local action of TGF-β1 in the joint, as suggested by animal studies of exogenous supplementation and endogenous inhibition of TGF-β1 (15
), suggest the potential usefulness of this marker as measured in synovial fluid. However, as the need for biomarkers is primarily to facilitate large, longitudinal studies and clinical trials of therapeutics, evening collections and invasive procedures such as arthrocentesis, even if stronger associations were seen, would make this marker impractical.
The strengths of our study are the inclusion of African American and Caucasian men and women and the collection of longitudinal radiographic data at two large joint sites over a mean of 6 years. This is the largest longitudinal study to date of TGF-β1 as a biomarker of rOA. Although we have observed higher levels of TGF-β1 among African American individuals, there is no race interaction for the relationship of rOA and TGF-β1, indicating no significant difference by race in the effect of this growth factor. Despite
the large size of our sample and the use of a joint-based analysis to maximize sample size for this longitudinal analysis, we did not identify significant associations between serum TGF-β1 levels and incident or progressive rOA at the hip or knee. This finding, in combination with the lack of association identified in our cross-sectional analysis, indicates that serum TGF-β1 is unlikely to be a robust biomarker of OA for future studies.